A perspective on the development and lack of interchangeability of the breast cancer intrinsic subtypes

Abstract

Breast cancer intrinsic subtypes (IS) are biologically distinct entities, characterized by specific natural gene expression patterns 1 , 2 . The most widely accepted IS are the Luminal A, Luminal B, HER2-Enriched, and Basal-like 3 (Fig. 1 ). These entities are prognostic and have potential therapeutic implications in both early-stage and advanced-stage hormone receptor-positive (HR+)/HER2-negative breast cancer 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 . However, the IS molecular classification is often misinterpreted, and immunohistochemistry (IHC)-based IS surrogates, or other molecular subtype definitions, are erroneously used interchangeably. This generates confusion for all the stakeholders involved, including scientists studying these biomarkers and physicians considering them for clinical decision-making. In this perspective, therefore, we provide readers with a historical overview of the discovery and clinical implementation of the IS, the main technical and biological differences among assays developed for their detection, and propose a specific and simple nomenclature for subtyping to avoid further confusion and disservice to patients. Fig. 1: Heatplot representing the original, non-commercial PAM50 intrinsic subtypes’ genes, and gene expression patterns. The alternative text for this image may have been generated using AI. Full size image Median centered unsupervised hierarchical clustering representing the breast cancer intrinsic subtypes (Luminal A, Luminal B, HER2-Enriched, Basal-like) and the Normal-like group, identified using the research-based PAM50 assay on the nCounter ® platform, in a set of 527 archived breast cancer fresh-frozen paraffin-embedded (FFPE) samples from Dr. Prat’s laboratory. Each column represents a single patient’s sample. The red color represents relatively high gene expression, green represents relatively low gene expression, and black represents median gene expression. The PAM50 gene list is reported on the right side of the heatplot. The unsupervised cluster and heatmap were obtained with R version 3.6.1, Cluster 3.0, and Javatreeview 1.1.6r4 for MacOSX. LumA luminal A, LumB luminal B, Her2 HER2-Enriched, Basal Basal-like, Normal Normal-like.

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